Identification of Rare LRP5 Variants in a Cohort of Males with Impaired Bone Mass

Osteoporosis is the most common bone disease characterized by reduced bone mass and increased bone fragility. Genetic contribution is one of the main causes of primary osteoporosis; therefore, both genders are affected by this skeletal disorder. Nonetheless, osteoporosis in men has received little a...

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Bibliographic Details
Published in:International journal of molecular sciences 2021-10, Vol.22 (19), p.10834
Main Authors: Rocca, Maria Santa, Minervini, Giovanni, Di Nisio, Andrea, Merico, Maurizio, Bueno Marinas, Maria, De Toni, Luca, Pilichou, Kalliopi, Garolla, Andrea, Foresta, Carlo, Ferlin, Alberto
Format: Article
Language:English
Subjects:
Bayesian analysis
Biomedical materials
Bone diseases
Bone growth
Bone mass
Bone mineral density
Fractures
Fragility
Genes
Genetic analysis
Genetic diversity
Genomes
Low density lipoprotein receptors
LRP5 protein
Males
Mutation
Next-generation sequencing
Osteogenesis
Osteoporosis
Phenotypes
Phosphorylation
Proteins
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Summary:Osteoporosis is the most common bone disease characterized by reduced bone mass and increased bone fragility. Genetic contribution is one of the main causes of primary osteoporosis; therefore, both genders are affected by this skeletal disorder. Nonetheless, osteoporosis in men has received little attention, thus being underestimated and undertreated. The aim of this study was to identify novel genetic variants in a cohort of 128 males with idiopathic low bone mass using a next-generation sequencing (NGS) panel including genes whose mutations could result in reduced bone mineral density (BMD). Genetic analysis detected in eleven patients ten rare heterozygous variants within the LRP5 gene, which were categorized as VUS (variant of uncertain significance), likely pathogenic and benign variants according to American College of Medical Genetics and Genomics (ACMG) guidelines. Protein structural and Bayesian analysis performed on identified LRP5 variants pointed out p.R1036Q and p.R1135C as pathogenic, therefore suggesting the likely association of these two variants with the low bone mass phenotype. In conclusion, this study expands our understanding on the importance of a functional LRP5 protein in bone formation and highlights the necessity to sequence this gene in subjects with idiopathic low BMD.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms221910834